Evidence that (-)-7-hydroxy-4 '-dimethylheptyl-cannabidiol activates a non-CB1, non-CB2, non-TRPV1 target in the mouse vas deferens

R G Pertwee, A Thomas, L A Stevenson, Y Maor, R Mechoulam

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Previous experiments showed that R-(+)-WIN55212-induced inhibition of electrically-evoked contractions of mouse vasa deferentia could be antagonized by cannabidiol in a manner that appeared to be competitive but not to involve direct competition for established cannabinoid receptors. We have now discovered that (-)-7-hydroxy-4'-dimethylheptyl-cannabidiol (7-OH-DMH-CBD) inhibits electrically-evoked contractions of the vas deferens (EC50 = 13.3 nM). This it appeared to do by acting on prejunctional neurotics as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or beta,gamma-methylene-ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB1 receptor antagonist than R-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 mu M; apparent K-B = 222.2 nM) but not by the CB, receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (I mu M) or capsazepine (10 mu M). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(+)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of G(i/o) proteins from CB1 receptors by alpha(2)-adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB1, CB2, TRPV1, opioid or alpha(2)-adrenergic receptor but do not exclude the possibility that it also activates CB1 receptors. (c) 2005 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)1139-1146
Number of pages8
JournalNeuropharmacology
Volume48
DOIs
Publication statusPublished - 2005

Keywords

  • (-)-7-hydroxy-4 '-dimethylheptyl-cannabidiol (7-OH-DMH-CBD)
  • cannabidiol
  • R-(+)-WIN55212
  • yohimbine
  • mouse vas deferens
  • G(i/o) protein sequestration
  • CANNABINOID RECEPTOR AGONISTS
  • MESENTERIC VASODILATION
  • CB2 RECEPTORS
  • CANNABIDIOL
  • NORADRENALINE
  • ANTAGONIST
  • ANANDAMIDE
  • RELEASE
  • PHARMACOLOGY
  • MODULATION

Cite this

Evidence that (-)-7-hydroxy-4 '-dimethylheptyl-cannabidiol activates a non-CB1, non-CB2, non-TRPV1 target in the mouse vas deferens. / Pertwee, R G ; Thomas, A ; Stevenson, L A ; Maor, Y ; Mechoulam, R .

In: Neuropharmacology, Vol. 48, 2005, p. 1139-1146.

Research output: Contribution to journalArticle

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abstract = "Previous experiments showed that R-(+)-WIN55212-induced inhibition of electrically-evoked contractions of mouse vasa deferentia could be antagonized by cannabidiol in a manner that appeared to be competitive but not to involve direct competition for established cannabinoid receptors. We have now discovered that (-)-7-hydroxy-4'-dimethylheptyl-cannabidiol (7-OH-DMH-CBD) inhibits electrically-evoked contractions of the vas deferens (EC50 = 13.3 nM). This it appeared to do by acting on prejunctional neurotics as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or beta,gamma-methylene-ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB1 receptor antagonist than R-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 mu M; apparent K-B = 222.2 nM) but not by the CB, receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (I mu M) or capsazepine (10 mu M). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(+)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of G(i/o) proteins from CB1 receptors by alpha(2)-adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB1, CB2, TRPV1, opioid or alpha(2)-adrenergic receptor but do not exclude the possibility that it also activates CB1 receptors. (c) 2005 Elsevier Ltd. All rights reserved.",
keywords = "(-)-7-hydroxy-4 '-dimethylheptyl-cannabidiol (7-OH-DMH-CBD), cannabidiol, R-(+)-WIN55212, yohimbine, mouse vas deferens, G(i/o) protein sequestration, CANNABINOID RECEPTOR AGONISTS, MESENTERIC VASODILATION, CB2 RECEPTORS, CANNABIDIOL, NORADRENALINE, ANTAGONIST, ANANDAMIDE, RELEASE, PHARMACOLOGY, MODULATION",
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AU - Stevenson, L A

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AU - Mechoulam, R

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N2 - Previous experiments showed that R-(+)-WIN55212-induced inhibition of electrically-evoked contractions of mouse vasa deferentia could be antagonized by cannabidiol in a manner that appeared to be competitive but not to involve direct competition for established cannabinoid receptors. We have now discovered that (-)-7-hydroxy-4'-dimethylheptyl-cannabidiol (7-OH-DMH-CBD) inhibits electrically-evoked contractions of the vas deferens (EC50 = 13.3 nM). This it appeared to do by acting on prejunctional neurotics as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or beta,gamma-methylene-ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB1 receptor antagonist than R-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 mu M; apparent K-B = 222.2 nM) but not by the CB, receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (I mu M) or capsazepine (10 mu M). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(+)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of G(i/o) proteins from CB1 receptors by alpha(2)-adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB1, CB2, TRPV1, opioid or alpha(2)-adrenergic receptor but do not exclude the possibility that it also activates CB1 receptors. (c) 2005 Elsevier Ltd. All rights reserved.

AB - Previous experiments showed that R-(+)-WIN55212-induced inhibition of electrically-evoked contractions of mouse vasa deferentia could be antagonized by cannabidiol in a manner that appeared to be competitive but not to involve direct competition for established cannabinoid receptors. We have now discovered that (-)-7-hydroxy-4'-dimethylheptyl-cannabidiol (7-OH-DMH-CBD) inhibits electrically-evoked contractions of the vas deferens (EC50 = 13.3 nM). This it appeared to do by acting on prejunctional neurotics as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or beta,gamma-methylene-ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB1 receptor antagonist than R-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 mu M; apparent K-B = 222.2 nM) but not by the CB, receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (I mu M) or capsazepine (10 mu M). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(+)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of G(i/o) proteins from CB1 receptors by alpha(2)-adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB1, CB2, TRPV1, opioid or alpha(2)-adrenergic receptor but do not exclude the possibility that it also activates CB1 receptors. (c) 2005 Elsevier Ltd. All rights reserved.

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KW - mouse vas deferens

KW - G(i/o) protein sequestration

KW - CANNABINOID RECEPTOR AGONISTS

KW - MESENTERIC VASODILATION

KW - CB2 RECEPTORS

KW - CANNABIDIOL

KW - NORADRENALINE

KW - ANTAGONIST

KW - ANANDAMIDE

KW - RELEASE

KW - PHARMACOLOGY

KW - MODULATION

U2 - 10.1016/j.neuropharm.2005.01.010

DO - 10.1016/j.neuropharm.2005.01.010

M3 - Article

VL - 48

SP - 1139

EP - 1146

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -